This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15- HL-101: Develop improved biocompatible surfaces for implantable blood-contacting medical devices. More than five million Americans, and increasingly more, suffer from heart failure yearly. Although cardiac transplantation is the best treatment for end-stage heart failure patients, not enough donor organs are available. Mechanical circulatory assist devices (MCADs) can reduce the risk of death and increase the quality of life for these patients;however, the contact of blood with their inner surface (usually titanium) often causes a coagulopathy resulting in bleeding and thrombosis. Local areas of low flow and blood stasis in most MCADs also contribute to the risk for thrombosis, especially in partial circulatory support devices that could benefit more than a million patients with less advanced heart failure. We hypothesize that a confluent lining of the patients'own endothelial progenitor cells (EPCs) will provide a more antithrombogenic and biocompatible surface and propose the following specific aims: Specific Aim 1: to genetically enhance endothelial progenitor cells, isolated from swine peripheral blood, by over-expressing the anticoagulant and anti-inflammatory protein thrombomodulin (TM) before the cells are seeded on the inside of titanium (Ti) tubes. Specific Aim 2: to surgically implant Ti tubes lined with either genetically enhanced (TM-EPC) or un-enhanced EPCs into the inferior vena cava of those pigs from which the EPCs were derived, and compare them to a group of pigs that undergoes implantation of uncoated, bare Ti tubes. A fourth group will be a control group undergoing sham operations only. Peripheral blood samples will be obtained at four time points from all pigs, and known markers of thrombosis and inflammation will be quantified with well-established bioassays. We hypothesize that known markers of thrombosis and inflammation, quantified from peripheral blood samples in these pigs, will demonstrate an improved biocompatibility of EPC-lined blood contacting surfaces. Furthermore, we anticipate that our genetically enhanced cells (TM-EPC) will render the titanium even less thrombogenic. Specific Aim 3: to perform analytical microarray-based proteomic analysis on all peripheral blood samples and to compare the four different groups and time points within each animal in order to determine the differential expression levels of a large number of known proteins associated with coagulation, fibrinolysis, inflammation and complement activation. We hypothesize that a subset of these specific proteins will reflect the effects of EPC seeding, as well as reveal differences between genetically enhanced TM-EPCs and bare Ti implants. The knowledge gained will extend our understanding of the biocompatibility of blood-contacting surfaces, and may give rise to a panel of novel biomarkers of biocompatibility of blood-contacting surfaces. According to the American Heart Association, that there are more than 5 million people living in the United States who are suffering from heart failure. Moreover, the prevalence of heart failure is steadily increasing, in part because of the aging of our population. Despite improvements in medical therapy, the mortality rate in these patients has remained extremely high, with a 5-year median survival rate of only 25% in men and 38% in women. In 2004 alone, there were over one million hospitalizations in the US with a first listed discharge diagnosis of heart failure. It is estimated that more than 250,000 of patients are in the terminal phases of this disease and suffering from severe symptoms, which cannot be alleviated even with maximal medical therapy. The results of our proposal may lead to a technology, which could alleviate the symptoms of more than one million of Americans by providing a biocompatible blood-contacting surface for mechanical circulatory assist devices for partial as well as full support of the failing heart. Furthermore, this technology could be applicable to other titanium /titanium-alloy blood-contacting surfaces, such as nitinol vascular stents. These could become resistant to in-stent restenosis and benefit millions of Americans who are being treated with coronary or vascular stents. PUBLIC HEALTH RELEVANCE: According to the American Heart Association, that there are more than 5 million people living in the United States who are suffering from heart failure. Moreover, the prevalence of heart failure is steadily increasing, in part because of the aging of our population. Despite improvements in medical therapy, the mortality rate in these patients has remained extremely high, with a 5-year median survival rate of only 25% in men and 38% in women. In 2004 alone, there were over one million hospitalizations in the US with a first listed discharge diagnosis of heart failure. It is estimated that more than 250,000 of patients are in the terminal phases of this disease and suffering from severe symptoms, which cannot be alleviated even with maximal medical therapy. The results of our proposal may lead to a technology, which could alleviate the symptoms of more than one million of Americans by providing a biocompatible blood-contacting surface for mechanical circulatory assist devices for partial as well as full support of the failing heart. Furthermore, this technology could be applicable to other titanium /titanium-alloy blood-contacting surfaces, such as nitinol vascular stents. These could become resistant to in-stent restenosis and benefit millions of Americans who are being treated with coronary or vascular stents.